Huntington's disease (HD) is an autosomal dominant, progressive, neurodegenerative disorder associated with selective neuronal cell death, occurring primarily in the cortex and striatum. The disorder is caused by a CAG codon repeat expansion in the first exon of a gene encoding a 350 kD protein, huntingtin, with unknown function (Ambrose et al., Somat Cell Mol. Genet. 20:27–38, 1994). CAG encodes the amino acid glutamine (“Gln” or “Q”), so CAG repeats encode polyglutamine regions within huntingtin. The polyglutamine region of huntingtin from non-HD individuals contains about 8–31 consecutive Gln residues. Huntingtin with over 37 consecutive Gln residues is associated with mild to severe HD, with the more severe cases exhibiting a polyglutamine region of up to about 68 Gln residues.
In addition to HID, at least six other inherited neurodegenerative disorders have been found to be associated with CAG expansions. Increasing the length of CAG repeats in the coding region of unrelated genes, and resulting polyglutamine regions in the encoded proteins, causes a similar pattern of neuron degeneration, indicating a similar, if not identical, mechanism of cell death. HD may be caused by abnormal protein-protein interactions mediated by elongated polyglutamines.